Please use this identifier to cite or link to this item :https://hdl.handle.net/2066/134037

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Subject:

Radboudumc 0: Other Research RIHS: Radboud Institute for Health SciencesRadboudumc 0: Other Research RIMLS: Radboud Institute for Molecular Life Sciences

Organization:

CardiologyHuman Genetics

Journal title:

Human Mutation

Volume:

vol. 35

Issue:

iss. 5

Page start:

p. 571

Page end:

p. 574

Abstract:

Marfan syndrome (MFS) is caused by mutations in the FBN1 (fibrillin-1) gene, but approximately 10% of MFS cases remain genetically unsolved. Here, we report a new FBN1 mutation in an MFS family that had remained negative after extensive molecular genomic DNA FBN1 testing, including denaturing high-performance liquid chromatography, Sanger sequencing, and multiplex ligation-dependent probe amplification. Linkage analysis in the family and cDNA sequencing of the proband revealed a deep intronic point mutation in intron 56 generating a new splice donor site. This mutation results in the integration of a 90-bp pseudo-exon between exons 56 and 57 containing a stop codon, causing nonsense-mediated mRNA decay. Although more than 90% of FBN1 mutations can be identified with regular molecular testing at the genomic level, deep intronic mutations will be missed and require cDNA sequencing or whole-genome sequencing.